Brain and Plasma Pharmacokinetics of Aripiprazole in Patients With Schizophrenia: An [ 18 F]Fallypride PET Study

Department of Psychiatry and Psychotherapy, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
American Journal of Psychiatry (Impact Factor: 12.3). 05/2008; 165(8):988-95. DOI: 10.1176/appi.ajp.2008.07101574
Source: PubMed


Aripiprazole at clinically effective doses occupies some 90% of striatal dopamine 2 and 3 (D(2)/D(3)) receptors. In order to further characterize its extrastriatal and time-dependent binding characteristics, the authors conducted positron emission tomography (PET) studies with the D(2)/D(3) antagonist [(18)F]fallypride at varying time points after the last aripiprazole administration in patients with schizophrenia.
Sixteen inpatients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder receiving treatment with aripiprazole underwent an [(18)F]fallypride PET scan. Receptor occupancy was calculated as the percentage reduction in binding potential relative to unblocked values measured in eight age-matched, medication-free patients with schizophrenia. In addition, aripiprazole serum concentrations were determined as part of a routine therapeutic drug monitoring program in a large group of patients (N=128) treated with aripiprazole.
Mean dopamine D(2)/D(3) receptor occupancy was high in all brain regions investigated, with no binding difference across brain regions. Nonlinear regression analysis revealed maximum attainable receptor occupancy (E(max)) values close to saturation. The values for serum concentration predicted to provide 50% of E(max) (EC(50)) were in the range of 5-10 ng/ml in all brain regions. The D(2)/D(3) receptors were completely saturated when serum aripiprazole concentration exceeded 100-150 ng/ml. The mean concentration in the large clinical patient sample was 228 ng/ml (SD=142).
Because of its high affinity for D(2)/D(3) receptors and its long elimination half-life, aripiprazole at clinical doses occupies a high fraction of its target receptor everywhere in the brain. Its dissociation from those receptors is very slow, such that the authors calculate from the results that in patients with serum aripiprazole concentrations in the range typical for clinical practice, D(2)/D(3) receptors must remain nearly saturated for as long as 1 week after the last dose.

    • "Blood samples, to measure plasma drug metabolite levels, were acquired 15 min before each scan and the estimated level of D2 receptor occupancy for the different antipsychotics was predicted using these plasma levels and Emax models. The Emax models (see below), based on putamen and caudate D2 receptor occupancies, using ED 50 and Emax for haloperidol [Fitzgerald et al., 2000] and aripiprazole [Grunder et al., 2008] were computed with the following formula: "
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    ABSTRACT: Antipsychotic drugs act on the dopaminergic system (first-generation antipsychotics, FGA), but some also directly affect serotonergic function (second-generation antipsychotics, SGA) in the brain. Short and long-term effects of these drugs on brain physiology remain poorly understood. Moreover, it remains unclear whether any physiological effect in the brain may be different for FGAs and SGAs. Immediate (+3.30 h) and different effects of single-dose FGA (haloperidol, 3 mg) and a SGA (aripiprazole, 10 mg) on resting cerebral blood flow (rCBF) were explored in the same 20 healthy volunteers using a pulsed continuous arterial spin labeling (pCASL) sequence (1.5T) in a placebo-controlled, repeated measures design. Both antipsychotics increased striatal rCBF but the effect was greater after haloperidol. Both decreased frontal rCBF, and opposite effects of the drugs were observed in the temporal cortex (haloperidol decreased, aripiprazole increased rCBF) and in the posterior cingulate (haloperidol increased, aripiprazole decreased rCBF). Further increases were evident in the insula, hippocampus, and anterior cingulate after both antipsychotics, in the motor cortex following haloperidol and in the occipital lobe the claustrum and the cerebellum after aripiprazole. Further decreases were observed in the parietal and occipital cortices after aripiprazole. This study suggests that early and different rCBF changes are evident following a single-dose of FGA and SGA. The effects occur in healthy volunteers, thus may be independent from any underlying pathology, and in the same regions identified as structurally and functionally altered in schizophrenia, suggesting a possible relationship between antipsychotic-induced rCBF changes and brain alterations in schizophrenia. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
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    • "The influence of hysteresis characteristics on EC 50 also suggests that if PD modeling is used alone, the concentration–occupancy relationship described by the model will vary according to the time points when the data are measured. For example, another study, which measured plasma concentration and receptor occupancy by aripiprazole at the times similar to ours, reported similar EC 50 (10±4(s.d.) ng/mL in putamen) (Grunder et al, 2008). In contrast, another study by the same group reported that a single ziprasidone dose resulted in occupancies exceeding the 95% prediction limits of the occupancy versus plasma concentrations for chronic doses, suggesting different concentration–occupancy relationship between single and chronic doses (Vernaleken et al, 2008). "
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    ABSTRACT: Positron emission tomography (PET) studies of dopamine receptor occupancy can be used to assess dosing of antipsychotics. Typically, studies of antipsychotics have applied pharmacodynamic (PD) modeling alone to characterize the relationship between antipsychotic dose and its effect on the brain. However, a limitation of this approach is that it does not account for the discrepancy between the time courses of plasma concentration and receptor occupancy by antipsychotics. Combined pharmacokinetic-PD (PK-PD) modeling, by incorporating the time dependence of occupancy, is better suited for the reliable analysis of the concentration-occupancy relationship. To determine the effect of time on the concentration-occupancy relationship as a function of analysis approach, we measured dopamine receptor occupancy after the administration of aripiprazole using [(11)C]raclopride PET and obtained serial measurements of the plasma aripiprazole concentration in 18 volunteers. We then developed a PK-PD model for the relationship, and compared it with conventional approach (PD modeling alone). The hysteresis characteristics were observed in the competitor concentration-occupancy relationship and the value of EC(50) was different according to the analysis approach (EC(50) derived from PD modeling alone=11.1 ng/mL (95% confidence interval (CI)=10.1 to 12.1); while that derived from combined PK-PD modeling=8.63 ng/mL (95% CI=7.75 to 9.51)). This finding suggests that PK-PD modeling is required to obtain reliable prediction of brain occupancy by antipsychotics.
    Preview · Article · Dec 2011 · Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism
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    • "If one considers that there also is a saturable concentration–effect relationship for SSRIs with respect to one of SSRI's most problematic side effect, i.e., serotonin syndrome severity (Hegerl et al. 1998), TDM could help to titrate the plasma levels of patients toward the minimum effective plasma concentrations to reduce side effect risk of the medication with almost no loss of effectiveness. Having expanded at length on an essentially monophasic hyperbolic relationship between plasma concentration– response relationship that most PET studies (Gründer et al. 2008; Meyer et al. 2004) also focus on, we hasten to add that at the upper end of the plasma concentration–response relationship, there may be a decrease a compound's overall therapeutic effect again, resulting in a biphasic plasma concentration–response relationship that may look like an inverted U. The paroxetine data shown in Fig. 5 may be considered as such an example, although the number of patients per 10 ng/ml bin at and above 105 ng/ml is far too small to allow any meaningful interpretation. "

    Full-text · Article · May 2011 · Psychopharmacology
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